Killing nearly 2 million people a year, TB is one of the leading causes of infectious disease deaths globally. In 2007, there were an estimated 9.27 million cases of TB. Co-infection with HIV and an increase in drug-resistant strains of TB are making the epidemic even more severe and complicated to address. The current TB vaccine, BCG, is almost 90 years old and has been ineffective in saving the millions of lives lost to TB each year. Aeras Global TB Vaccine Foundation is a non-profit Product Development Partnership working in collaboration with leading researchers and scientists from the academic, industry, non-profit and government sectors to develop new and effective vaccine regimens to stop TB. An increasingly well documented defect in the BCG vaccine lies in its inability to escape the phagolysosome of infected macrophages and dendritic cells, which, unlike M. tuberculosis or M. leprae, diverts the immune response to primarily MHC class II antigen presentation and is the likely reason for the CD4 dominant T cell response to vaccination. Loss and gain of function screens using M. tuberculosis and the related avirulent M. kansasii have identified specific genes present in Mtb complex organisms, including BCG, whose gene products function to inhibit apoptosis of infected macrophages. Aeras will create fully cGxP compliant recombinant BCG vaccines incorporating deletions in genes known to inhibit apoptosis to enhance immune responses by cross-priming and will also construct cGxP compliant booster vaccines encoding and expressing high valency CD8+ T cell immunogens to create an optimal tuberculosis vaccine regimen. The booster vaccines will consist of recombinant adenovirus serotype 4 and recombinant human CMV vectors, both of which have been shown to elicit potent CD8+ T cell responses. We will evaluate these regimens in mice and rhesus macaques, models of TB vaccine immunology and efficacy with which we have extensive experience, to expediently select an optimal regimen.